This proposal describes a five-year research and training plan that will facilitate the transition of Dr. Ajay Sheshadri, MD to an independent academic researcher. Ajay has a strong background in clinical research and medicine and has completed post-graduate training in Internal Medicine and Pulmonary/Critical Care Medicine. The primary goal of this proposal is to provide the framework and support necessary for Dr. Sheshadri to fulfill his career goals as a clinical investigator through transition to independent scientific investigation in the use of advanced imaging in obstructive airway diseases. The proposed research plan will focus on a patient-based approach to identifying clinical and imaging predictors of response to bronchial thermoplasty in severe asthma. Bronchial thermoplasty is a novel device-based therapy that decreases airway smooth muscle through the use of radiofrequency energy in severe asthma, decreasing exacerbation rates and improving quality of life. The proposed study will enroll patients with severe asthma over three years and characterize them in detail using multiple clinical and novel imaging modalities. These variables will then be used to determine predictors of response to bronchial thermoplasty as defined by a reduction in corticosteroid dose or improvement in asthma- specific quality of life. Aim 1 focuses on identifying clinical predictors of response to bronchial thermoplasty by measuring the following before and 12 months after bronchial thermoplasty: pulmonary function tests, methacholine bronchoprovocation, sputum inflammation, exhaled nitric oxide, asthma-specific quality of life, asthma control, oral and inhaled steroid dose, and healthcare utilization. This clinical characterization of subjects will help us test the hypothesis that patients with lower baseline quality of life are more likely to have a reduction in oral or inhaled steroid dose after bronchial thermoplasty. Aim 2 focuses on the use of novel quantitative measures of airway wall thickness and lung densitometry to determine predictors of improvement in quality of life after bronchial thermoplasty. This imaging characterization of subjects will help us test the hypothesis that patients with more small airway disease, as measured by increased air trapping on CT, are less likely to have an adequate response to bronchial thermoplasty. Our extensive experience in standardizing imaging acquisition and analysis for use in quantitative studies of severe asthma allow for high-fidelity analyses of imaging predictors of response to bronchial thermoplasty that have not been described in the literature. Together, these aims will allow for an extensive characterization of patients with severe asthma with the goal of revealing responder and non-responder phenotypes to predict response to a specific therapy. The proposed application will allow Dr. Sheshadri to develop a high-level research career focused on developing novel quantitative imaging techniques to augment phenotypic characterization of obstructive airway diseases.